Synthesis of r(+)α-lipoic acid

ABSTRACT

Process for the synthesis of R(+)α-lipoic acid comprising the following stages: a) Salifying of racemic 6,8-halo-octanoic acid with S(−)α-methylbenzylamine; b) separation by filtration of the crystallized diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(−)α-methylbenzylamine; c) purification by re-crystallization of the diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(−)α-methylbenzylamine; (d) separation of the diastereoisomeric salt to obtain R(+)6,8-di-halo-octanoic acid by reation of said salt with strong mineral acids in an aqueous solution with a dilution between 2 and 10% by weight; e) esterification of R(+)6,8-di-halo-octanoic acid to obtain the corresponding alkyl ester; f) reaction of the alkyl ester of R(+)6,8-di-halo-octanoic acid in an organic solvent with an aqueous solution of alkali disulfide in presence of a compound for phase transfer catalysis; g) hydolysis of the ester of R(+)α-lipoic acid.

FIELD OF THE INVENTION

The present invention relates to a process of synthesis of R(+)α-lipoicacid through the formation of diastereoisomeric salts of racemic6,8-di-halooctanoic acid with optic isomers of α-methylbenzylamine,separation of R(+)-dihalooctanoic acid and its transformation into thecorresponding α-lipoic acid with phase transfer catalysis.

STATE OF THE ART

It is well known from the state of the art the process of resolution ofracemic mixtures, or racemates, i.e. the splitting of a racemate intothe enantiomers constituting it. The racemate is first transformed intoa mixture of diastereoisomers by reaction with an optically activesubstance. The diastereoisomers thus obtained, characterized bydifferent physical properties among which solubility, are generallyseparated by fractioned crystallization. The enantiomers of the startingracemic mixture are obtained from said separated diastereoisomers bysimple chemical reactions of separation of said diastereoisomers.

U.S. Pat. No. 5,281,722 describes diastereoisomeric salts obtained frompure enantiomers of α-lipoic acid by reaction with optic isomers ofα-methylbenzylamine. Knows procedures describe methods for thepreparation of said diastereoisomeric salts and their use asintermediate products in the resolution of a racemic mixture of thiocticacid in both optically active enantiomeric forms R(+) and S(−) ofα-lipoic acid. The process of resolution of racemic thioctic acid has alow yield, in particular for the separation of the R(+)α-lipoicenantiomer (see Examples 7 and 8 of U.S. Pat. No. 5,281,722).

As a matter of fact, the purification processes described at the stateof the art for diastereoisomeric salts have a low enantiomericenrichment of the salt of the R(+)α-lipoic isomer. This is furtherconfirmed by the high number of re-crystallizations carried out ondiastereoisomeric salts before the scission reaction with acids.

Tests carried out by the Applicant show that the scission of thepurified diastereoisomeric salts by addition of inorganic acids, forinstance mineral acids such as 1N hydrochloric acid, to obtain the twoseparated optically active enantiomeric forms R(+) and S(−) of α-lipoicacid, as described in U.S. Pat. No. 5,281,722, results in low-qualityenantiomers of α-lipoic acid (presence of polymers).

The state of the art describes the use of diastereoisomeric saltsobtained from the enantiomers of α-lipoic acid by means of reaction withoptically active bases in order to separate the isomers R(+) and S(−) ofα-lipoic acid. However, the processes described at the state of the art,as verified by the Applicant, are characterized by complex and longmethods for purifying intermediate diastereoisomeric salts, with lowyields of resolution of racemates as well as an unsatisfying quality ofthe optic isomers thus obtained.

There was therefore a need for a process of synthesis of the opticisomer R(+) of α-lipoic acid which could represent an alternative toprocesses at the state of the art comprising as intermediate product ofreaction racemic thioctic acid. In particular, there was a need forsynthesis processes which could give a high quality and high purityoptic isomer of α-lipoic acid with higher yields.

SUMMARY

It has now been found a new process of synthesis of R(+)α-lipoic acidthrough the resolution of racemic 6,8-di-halo-octanoic acid with theoptically active base (S)-α-methylbenzylamine and the reaction with thealkali disulfide of the corresponding esterified enantiomer alkaliR(+)6,8-di-halooctanoate by phase transfer catalysis, said processovercoming the disadvantages characterizing the processes at the stateof the art, such as complexity, low yield and low quality of theobtained optic isomers.

Quite unexpectedly and surprisingly, the Applicant has found a newprocess of synthesis of R(+)α-lipoic acid by salification of6,8-di-halo-octanoic acid with the optically active baseS(−)α-methylbenzylamine to obtain the diastereoisomeric salt of(+)-6,8-di-halo-octanoic acid-S(−)α-methylbenzylamine, followed by itspurification by fractioned crystallization and scission of the salt withacids, thus obtaining the enantiomer (+)-6,8-di-halooctanoic acid,which, after being esterified, is reacted by phase transfer catalysiswith aqueous solutions of alkali disulfide in order to obtain esterifiedR(+)α-lipoic acid.

DETAILED DESCRIPTION OF THE INVENTION

An object of the present invention is therefore a process of synthesisof R(+)α-lipoic acid comprising the following stages:

-   a) salifying of racemic 6,8-halooctanoic acid with    S(−)α-methylbenzylamine, wherein the molar ratio    S(−)α-methylbenzylamine/racemic 6,8-di-halooctanoic acid is between    0.45 and 0.65;-   b) separation by filtration of the crystallized diastereoisomeric    salt of R(+)6,8-dihalo-octanoic acid-S(−)α-methylbenzylamine;-   c) purification by re-crystallization of the diastereoisomeric salt    of R(+)6,8-di-halooctanoic acid-S(−)α-methylbenzylamine;-   d) separation of the diastereoisomeric salt to obtain    R(+)6,8-di-halooctanoic acid by reaction of said salt with strong    mineral acids in an aqueous solution with a dilution between 2 and    10% by weight;-   e) esterification of R(+)6,8-di-halo-octanoic acid to obtain the    corresponding alkyl ester;-   f) reaction of the alkyl ester of R(+)6,8-di-halo-octanoic acid in    an organic solvent with an aqueous solution of alkali disulfide in    presence of a compound for phase transfer catalysis selected from    the group consisting of quaternary ammonium or phosphonium salts    having the following general formula:    -   where:    -   A is nitrogen or phosphorus,    -   X is selected from the group consisting of Cl, Br, I, HSO₄ e        H₂PO₄, and the substituents R₁, R₂, R₃ e R₄ are selected from        the group consisting of linear or branched alkyl radicals having        one to twenty carbon atoms (C₁-C₂₀), said substituents being        identical or different one from the other, or only one of said        substituents is selected from the group consisting of arylalkyl        radicals having the following formula —(CH₂)_(n)C₆H₅ in which        n=1-16;-   g) hydrolysis of the ester of R(+)α-lipoic acid.

The halogen substituents of the racemic 6,8-di-halo-octanoic acid,identical or different one from the other, are selected from the groupconsisting of Cl, Br or I.

Said racemic 6,8-di-halo-octanoic acid is preferably6,8-dichlorooctanoic acid, a product which can be easily found on themarket, produced according to the description contained in J.A.C.S.Volume 79, 1957, pages 6483-6487.

According to the process of synthesis described in the presentinvention, in salifying stage a) the molar ratioS(−)α-methylbenzylamine/racemic 6,8-di-halooctanoic acid is preferablybetween 0.48 and 0.60, still more preferably between 0.50 and 0.58. Thesalifying in stage a) is carried out at atmospheric pressure in anorganic solvent, preferably ethyl acetate, at a temperature between 20and 40° C., preferably between 25 and 30° C. The concentration ofracemic 6,8-di-halooctanoic acid in salification stage a) is between 10and 40% w/v, preferably between 15 and 35% w/v, still more preferablybetween 20 and 30% w/v of solvent.

Stage b), i.e. separation by filtration of the diastereoisomeric salt,takes place at a temperature of 0 to 10° C., preferably at 2° C.

In stage c), i.e. purification by recrystallization of thediastereoisomeric salt of R(+)6,8-di-halooctanoicacid-S(−)α-methylbenzylamine, the solvents used are alkyl esters ofaliphatic or aromatic carboxylic acids, in which alkyl is C₁-C₃,preferably alkyl esters of aliphatic carboxylic acids having 2 to 4carbon atoms, heating at a temperature between 40 and 65° C., preferablybetween 45 and 60° C., still more preferably between 50 and 55° C.

In stage d), i.e. separation of the diastereoisomeric salt, the aqueousmineral acid is preferably sulfuric acid with a dilution between 4 and8% by weight, still more preferably sulfuric acid is diluted to 5% byweight.

Stage e), i.e. esterification of R(+)6,8-di-halo-octanoic acid,comprises a reaction of esterification according to methods well knownin the field of esterification of aliphatic carboxylic acids withaliphatic or aromatic alcohols.

According to the present invention alkyl esters ofR(+)6,8-di-halo-octanoic acid are linear or branched C₁-C₆ esters,preferably linear or branched C₁-C₃ esters, still more preferably methylester and ethyl ester.

According to the present invention the amount of alkyl esters ofR(+)6,8-di-halo-octanoic acid in the reaction taking place in stage f)is between 5 and 60% by weight, preferably between 10 to 40% by weight,still more preferably between 15 to 30% by weigh with respect to theorganic solvent.

The organic solvent used in the reaction taking place in stage f) is asolvent which cannot be mixed with water, selected from the groupconsisting of: linear or branched aliphatic C₅-C₁₀ hydrocarbons, oraromatic C₅-C₁₀ hydrocarbons also having substituting groups selectedfrom the group consisting of halogen, nitro or nitrile groups; esters ofaliphatic or aromatic carboxylic acids; linear or cyclic ethers, linearor cyclic C₄-C₁₀ ketones; carbon disulfide; carbon tetrachloride. Thesolvent is preferably benzene or toluene.

The process for the synthesis of R(+)α-lipoic acid according to presentinvention comprises the phase transfer of the disulfide ion from theaqueous solution containing the corresponding alkali disulfide to theorganic phase which cannot be mixed with water, containing the alkylester of R(+)6,8-di-halo-octanoic acid. The aqueous solution of alkalidisulfide can be prepared by reacting in water sulfur (S) with thecorresponding alkali sulfide.

Preferred alkali disulfides are sodium disulfide (Na₂S₂) and potassiumdisulfide (K₂S₂) or their mixtures, still more preferred sodiumdisulfide.

In the reaction taking place in stage f) of the process of synthesis ofR(+)α-lipoic acid according to the present invention, the molar ratioalkali disulfide/alkyl ester of R(+)6,8-di-halo-octanoic acid is between0.8 and 1.2, preferably between 0.9 and 1.1, still more preferablybetween 0.95 and 1.0.

The preferred compounds for phase transfer catalysis used for thesynthesis of R(+)α-lipoic acid which is the object of the presentinvention, are selected from the group consisting of tetrabutylammoniumbromide, tetrabutylphosphonium bromide, methyltrioctylammonium chloride(ALIQUAT® 336), methyl-(C₈-C₁₀)-trialkylammonium chloride (ADOGEN® 464)and tetrabutylammonium hydrogensulfate; still more preferred aretetrabutylammonium bromide and tetrabutylammonium hydrogensulfate.

According to the process of synthesis described in the presentinvention, in the reaction taking place in stage f) the compound forphase transfer catalysis, a quaternary salt, is present in an amountbetween 0.5 to 10% in moles, preferably between 1 to 5% in moles, stillmore preferably between 2 and 4% in moles with respect to the alkylester of 6,8-di-halo-octanoic acid.

The temperature of the reaction taking place in stage f) is between 20and 130° C., preferably between 60 and 100° C., still more preferablybetween 80 and 90° C. Stage g), i.e. hydrolysis of the ester ofR(+)α-lipoic acid, is a hydrolysis with alkali/alcaline-earth hydroxidesin presence of organic solvents, such as alcohols and polyols, ethersand hydroxy ethers, ketones and hydroxy ketones, which can be mixed withwater in a volume ratio of 50:50 to 95:5 at a temperature between 0 and100° C. The concentration of the ester with respect to the organicsolvent is between 5 and 50% w/v and the molar ratio ester/hydroxide isbetween 0.5 and 1. Free R(+)α-lipoic acid can be recovered by treatmentwith aqueous mineral acids diluted 1 to 20% by weight or water-solubleorganic acids.

Reaction products and intermediate products are characterized with¹H-NMR, Mass and HPLC analyses.

The following area some examples disclosing though not limiting thepresent invention.

EXAMPLE 1

a) 40 g (0.187 moles) of racemic 6,8-dichlorooctanoic acid are dissolvedin 150 ml of ethyl acetate at 25-30° C. This solution is added with 12.3g (0.101 moles) of S(−)α-methylbenzylamine. Said solution is cooled downfirst at 18-20° C. until the precipitation starts, and then at 0-5° C.The solid obtained is filtered, washed with ethyl acetate (10 ml), thusobtaining 15.3 g of humid salt of (+)-6,8-dichlorooctanoicacid-S(−)α-methylbenzylamine.

b) The mother liquors resulting from the crystallization taking place instage a) are extracted with 100 ml of sulfuric acid at 5% by weight,checking that the pH value of the aqueous phase is 1. The organic phaseis washed twice with 20 ml of water, then concentrated by solventdistillation at atmospheric pressure until reaching a volume of 130-140ml. The solution is added with 9.75 g (0.08 moles) ofR(+)α-methylbenzylamine, cooled down first at 18-20° C. until theprecipitation starts, and then at 0-5° C. The solid is filtered andwashed with 10 ml of ethyl acetate, thus obtaining 8.2 g of humid saltof (−)-6,8-dichlorooctanoic acid-R(+)α-methylbenzylamine.

c) The mothers liquors resulting from the crystallization taking placein stage b) are extracted with 50 ml of sulfuric acid 5% by weight,checking that the pH value of the aqueous phase is ≦1. The organic phaseis washed twice with 20 ml of water, then concentrated by solventdistillation at atmospheric pressure until reaching a volume of 40-45ml. The solution is added with 50 ml of ethyl acetate and 9.8 g (0.081moles) of S(−)α-methylbenzylamine, cooled down first at 18-20° C. untilthe precipitation starts, and then at 0-5° C. The solid is filtered andwashed with 10 ml of ethyl acetate, thus obtaining 12 g of humid salt of(+)-6,8-dichlorooctanoic acid-S(−)α-methylbenzylamine.

d) The humid salts of (+)-6,8-dichlorooctanoicacid-S(−)α-methylbenzylamine obtained in stages a) and c) are united andcrystallized two times, each time with 55 ml of ethyl acetate. 16 g ofhumid product are obtained and dried under vacuum, thus obtaining 13.5 gof the salt of (+)-6,8-dichlorooctanoic acid-S(−)α-methylbenzylamine.Said salt is suspended in a mixture of water (60 ml) and toluene (60 ml)and acidified with sulfuric acid at 5% by weight until pH=1. The organicphase is separated and concentrated under vacuum, thus obtaining 9 g of(+)-6,8-dichlorooctanoic acid (yield=45%).

[α]²⁴ _(D)=26.7 (c=2, ethanol).

EXAMPLE 2

9 g (0.042 moles) of (+)-6,8-dichlorooctanoic acid are dissolved in 120ml of methanol containing 0.45 ml of aqueous hydrochloric acid at 37% byweight. The solution is refluxed for two hours, the solvent isevaporated at reduced pressure, 17 ml of toluene are added and theobtained solution is washed twice with 10 ml of water. The toluene phaseis concentrated under vacuum, thus obtaining 9.4 g of methyl(+)-6,8-dichlorooctanoate (yield=98.6%).

[α]²⁰ _(D)=26.5 (c=1, toluene).

EXAMPLE 3

A mixture consisting of 5.65 g (0.043 moles) of sodium sulfide 60% byweight, 1.18 g (0.037 moles) of sulfur and 20 ml of water is heated at85° C. for 30 minutes. After being filtered to remove the insolubleportion, the solution is added in three hours to a solution consistingof 9.4 (0.041 moles) of methyl (+)-6,8-dichlorooctanoate, 0.37 g (0.0011moles) of tetrabutylammonium bromide and 18.5 ml of toluene, kept at 82°C. The mixture is refluxed (90° C.) for 1 hour and cooled down at 30°C., the organic phase is separated and washed with 5 ml of water. Thewhole is concentrated under vacuum, thus obtaining 8.6 g of methyl esterof R(+)α-lipoic acid (yield=94.4%).

The final product is characterized by means of ¹H-NMR and Mass analyses:

¹H-NMR—δ (300 MHz, CDCl₃): 1.4 (2H, m); 1.67 (4H, m); 1.83 (1H, td);2.24 (2H, t); 2.4 (1 H, td); 3.1 (2H, m); 3.5 (1H, m); 3.66 (3H, s).

Mass (EI): 220 (M⁺); 189 (—CH₃O).

[α]²⁰ _(D)=88 (c=1.8 toluene).

EXAMPLE 4

8.6 g (0.039 moles) of methyl ester of R(+)α-lipoic acid are added to asolution consisting of 2.36 g (0.042 moles) of potassium hydroxide at90% by weight, 19 ml of methanol and 3.8 ml of water. The mixtureobtained is heated at 50° C. for 2 hours, cooled down at 30° C. andadded with 40 ml of toluene. The whole is acidified with phosphoric acid10% by weight, keeping temperature below 30° C. The organic phase isseparated and washed three times, each time with 10 ml of an aqueoussolution of sodium chloride at 10% by weight. The solution isde-hydrated on sodium sulfate and concentrated to dryness by solventevaporation under vacuum. 3.3 ml of ethyl acetate and 41 ml ofcyclohexane are added, the solution is heated at 40° C. and treated withdecolorizing carbon, and the clear solution obtained is slowly cooleddown at 0° C. The solid is filtered and washed with 5 ml of cyclohexane,thus obtaining 3.6 g of R(+)α-lipoic acid (yield=45%).

[α]²⁰ _(D)=119.1 (c=1, ethanol).

e.e.>99% (HPLC).

1. Process for the synthesis of R(+)α-lipoic acid comprising thefollowing stages: a) Salifying of racemic 6,8-halo-octanoic acid withS(−)α-methylbenzylamine, in which the molar ratioS(−)α-methylbenzylamine/racemic 6,8-di-halo-octanoic acid is between0.45 and 0.65; b) separation by filtration of the crystallizeddiastereoisomeric salt of R(+)6,8-di-halo-octanoicacid-S(−)α-methylbenzylamine; c) purification by re-crystallization ofthe diastereoisomeric salt of R(+)6,8-di-halo-octanoicacid-S(−)α-methylbenzylamine; d) separation of the diastereoisomericsalt to obtain R(+)6,8-di-halo-octanoic acid by reaction of said saltwith strong mineral acids in an aqueous solution with a dilution between2 and 10% by weight; e) esterification of R(+)6,8-di-halo-octanoic acidto obtain the corresponding alkyl ester; f) reaction of the alkyl esterof R(+)6,8-di-halo-octanoic acid in an organic solvent with an aqueoussolution of alkali disulfide in presence of a compound for phasetransfer catalysis selected from the group consisting of quaternaryammonium or phosphonium salts having the following general formula:

where: A is nitrogen or phosphorus, X is selected from the groupconsisting of Cl, Br, I, HSO₄ e H₂PO₄, and the substituents R₁, R₂, R₃ eR₄ are selected from the group consisting of linear or branched alkylradicals having one to twenty carbon atoms (C₁-C₂₀), said substituentsbeing identical or different one from the other, or only one of saidsubstituents is selected from the group consisting of arylalkyl radicalshaving the following formula —(CH₂)_(n)C₆H₅ in which n=1-16; g)hydrolysis of the ester of R(+)α-lipoic acid.
 2. Process according toclaim 1, wherein said halogen substituents of racemic6,8-di-halo-octanoic acid, identical or different one from the other,are selected from the group consisting of Cl, Br or I.
 3. Processaccording to claim 2, wherein the racemic 6,8-di-halo-octanoic acid is6,8-dichloroctanoic acid.
 4. Process according to claim 1, wherein insalifying stage a) the molar ratio S(−)α-methylbenzylamine/racemic6,8-di-halo-octanoic acid is between 0.48 and 0.60.
 5. Process accordingto claim 4, wherein the molar ratio S(−)α-methylbenzylamine/racemic6,8-di-halo-octanoic acid is between 0.50 and 0.58.
 6. Process accordingto claim 1, wherein the concentration of racemic 6,8-di-halo-octanoicacid in salifying stage a) is between 10 and 40% w/v of solvent. 7.Process according to claim 6, wherein the concentration of racemic6,8-di-halo-octanoic acid is between 15 and 35% w/v of solvent. 8.Process according to claim 7, wherein the concentration of racemic6,8-di-halo-octanoic acid is between 20 and 30% w/v of solvent. 9.Process according to claim 1, wherein in stage d), i.e. separation ofthe diastereoisomeric salt, the aqueous mineral acid is sulfuric acidwith a dilution between 4 and 8% by weight.
 10. Process according toclaim 9, wherein sulfuric acid is diluted to 5% by weight.
 11. Processaccording to claim 1, wherein said alkyl esters ofR(+)6,8-di-halo-octanoic acid are linear or branched C₁-C₆ esters. 12.Process according to claim 11, wherein said alkyl esters ofR(+)6,8-di-halo-octanoic acid are linear or branched C₁-C₃ esters. 13.Process according to claim 12, wherein said alkyl esters ofR(+)6,8-di-halo-octanoic acid are methyl ester or ethyl ester. 14.Process according to claim 1, wherein the amount of alkyl esters ofR(+)6,8-di-halo-octanoic acid in the reaction taking place in stage f)is between 5 and 60% by weight with respect to the organic solvent. 15.Process according to claim 14, wherein the amount of alkyl esters ofR(+)6,8-di-halo-octanoic acid is between 10 and 40% by weight withrespect to the organic solvent.
 16. Process according to claim 15,wherein the amount of alkyl esters of R(+)6,8-di-halo-octanoic acid isbetween 15 and 30% by weight with respect to the organic solvent. 17.Process according to claim 1, wherein the organic solvent used in thereaction taking place in stage f) is a solvent which cannot be mixedwith water, selected from the group consisting of: linear or branchedaliphatic C₅-C₁₀ hydrocarbons, or aromatic C₅-C₁₀ hydrocarbons alsohaving substituting groups selected from the group halogen, nitro ornitrile groups, esters of aliphatic or aromatic carboxylic acids; linearor cyclic ethers; linear or cyclic C₄-C₁₀ ketones; carbon disulfide;carbon tetrachloride.
 18. Process according to claim 17, wherein saidsolvent is benzene or toluene.
 19. Process according to claim 1, whereinthe alkali disulfides are sodium disulfide (Na₂S₂) or potassiumdisulfide (K₂S₂) or their mixtures.
 20. Process according to claim 19,wherein said alkali disulfide is sodium disulfide.
 21. Process accordingto claim 1, wherein in the reaction taking place in stage f) the molarratio alkali disulfide/alkyl ester of R(+)6,8-di-halo-octanoic acid isbetween 0.8 and 1.2.
 22. Process according to claim 21, wherein saidmolar ratio is between 0.9 and 1.1.
 23. Process according to claim 22,wherein said molar ratio is between 0.95 and 1.0.
 24. Process accordingto claim 1, wherein the quaternary ammonium or phosphonium salts areselected from the group consisting of tetrabutylammonium bromide,tetrabutylphosphonium bromide, methyltrioctylammonium chloride (ALIQUAT®336), methyl-(C₈-C₁₀)-trialkylammonium chloride (ADOGEN® 464) andtetrabutylammonium hydrogensulfate.
 25. Process according to claim 24,wherein said quaternary salts are tetrabutylammonium bromide ortetrabutylammonium hydrogensulfate.
 26. Process according to claim 1,wherein the quaternary ammonium or phosphonium salt is present in anamount of 0.5 to 10% in moles with respect to the alkyl ester of6,8-di-halo-octanoic acid.
 27. Process according to claim 26, whereinsaid quaternary salt is present in an amount of 1 to 5% in moles withrespect to the alkyl ester of 6,8-di-halo-octanoic acid.
 28. Processaccording to claim 27, wherein said quaternary salt is present in anamount of 2 to 4% in moles with respect to the alkyl ester of6,8-di-halo-octanoic acid.
 29. Process according to claim 1, wherein thetemperature of the reaction taking place in stage f) is between 20 and130° C.
 30. Process according to claim 29, wherein said temperature isbetween 60 and 100° C.
 31. Process according to claim 30, wherein saidtemperature is between 80 and 90° C.